The present invention relates to certain compounds of the formula (I) depicted below, which are .beta.-adrenergic receptor agonists and accordingly have utility as, inter alia, hypoglycemic and antiobesity agents. More specifically, the compounds of the instant invention are selective agonists of the .beta..sub.3 -adrenergic receptor. The invention also relates to methods of use for the compounds and to compositions containing them. The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving the lean meat to fat ratio in animals, e.g. ungulate animals, companion animals, especially dogs, and poultry.
The compounds of this invention further possess utility in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders such as asthma and obstructive lung disease.
The disease diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type II diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
The compounds of the present invention and the pharmaceutically acceptable salts thereof effectively lower blood glucose levels when administered to mammals with hyperglycemia or diabetes.
The compounds of the present invention also reduce body weight or decrease weight gain when administered to animals. The ability of these compounds to affect weight gain is due to activation of .beta..sub.3 -adrenergic receptors which stimulate the metabolism of adipose tissue.
.beta.-Adrenergic receptors have been categorized into .beta..sub.1 -, .beta..sub.2 - and .beta..sub.3 -subtypes. Agonists of .beta.-receptors promote the activation of adenyl cyclase. Activation of .beta..sub.1 -receptors invokes increases in heart rate while activation of .beta..sub.2 -receptors induces relaxation of skeletal muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of .beta..sub.3 -receptors is known to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids) and metabolic rate (energy expenditure), and thereby promote the loss of fat mass. Compounds that stimulate .beta..sub.3 -receptors are therefore useful as anti-obesity agents, and can also be used to increase the content of lean meat in animals. In addition, compounds which are .beta..sub.3 -receptor agonists have hypoglycemic or anti-diabetic activity, but the mechanism of this effect is uncertain.
Until recently .beta..sub.3 -adrenergic receptors were thought to be found predominantly in adipose tissue. .beta..sub.3 -receptors are now known to be located in such diverse tissues as the intestine (J. Clin. Invest, 91, 344 (1993)) and the brain (Eur. J. Pharm., 219,193 (1992)). Stimulation of the .beta..sub.3 -receptor has been demonstrated to cause relaxation of smooth muscle in colon, trachea and bronchi. Life Sciences, 44(19), 1411 (1989); Br. J. Pharm., 112, 55 (1994); Br. J. Pharmacol., 110, 1311 (1993). For example, stimulation of .beta..sub.3 -receptors has been found to induce relaxation of histamine-contracted guinea pig ileum, J. Pharm. Exp. Ther., 260, 1, 192 (1992).
The .beta..sub.3 -receptor is also expressed in human prostate. Because stimulation of the .beta..sub.3 -receptor causes relaxation of smooth muscles that have been shown to express the .beta..sub.3 -receptor (e.g., intestine), one skilled in the art would predict relaxation of prostate smooth muscle. Therefore .beta..sub.3 -agonists are useful for the treatment or prevention of prostate disease.
U.S. Pat. No. 5,061,727 concerns certain substituted 5-(2-((2-aryl-2-hydroxyethyl)amino)-propyl)-1,3-benzodioxoles which are disclosed to possess anti-diabetic and/or anti-hyperglycemic and/or anti-obesity properties.
European Patent publication 516,349, published Dec. 2, 1992, refers to certain 2-hydroxyphenethyl amines which possess antiobesity, hypoglycemic and related utilities.
U.S. Pat. No. 4,358,455 is concerned with certain heterocyclic compounds of the formula Het-CHOH--CH.sub.2 --NH-aralkyl, useful for treating glaucoma and cardiovascular disorders.
U.S. Pat. No. 5,030,640 concerns certain .alpha.-heterocyclic ethanol amino alkyl indoles, useful as growth promoters, bronchodilators, antidepressants and antiobesity agents.
U.S. Pat. No. 5,019,578 concerns certain .alpha.-heterocyclic ethanol amines useful as growth promoters.